Methods of administering sorafenib to lactating women

Abstract

In accordance with some embodiments, provided herein is a method for reducing the likelihood of an adverse event caused by sorafenib in an infant fed from breast milk obtained from a subject treated with sorafenib, comprising: orally administering sorafenib to the subject at a daily dose of from about 37.5 mg to about 300 mg; and feeding the infant with breast milk from the subject for at least about 5 hours after administration of the sorafenicol to the subject, thereby reducing the likelihood of a sorafenicol adverse event in the infant.

Description

[0001] Priority Declaration

[0002] This application claims the benefit of U.S. Application No. 18 / 148,682, filed December 30, 2022, now U.S. Patent No. 11,771,666; U.S. Application No. 18 / 176,816, filed March 1, 2023, now U.S. Patent No. 11,771,667; U.S. Application No. 18 / 176,855, filed March 1, 2023, now U.S. Patent No. 11,793,776; U.S. Application No. 18 / 176,860, filed March 1, 2023, now U.S. Patent No. 11,779,554; U.S. Application No. 18 / 176,871, filed May 24, 2023, now U.S. Patent No. 11,779,554; No. 18 / 491,319, filed on October 20, 2023; the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to methods of administering solriamfetol to a lactating subject while reducing the likelihood of adverse events attributable to solriamfetol in a breastfed infant from the subject. Background Art

[0004] Soanfitol is a selective dopamine and norepinephrine reuptake inhibitor (DOPI) approved in the US for improving wakefulness in adults with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Soanfitol has been shown to treat a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, and fibromyalgia.

[0005] Pharmacokinetic studies have demonstrated rapid absorption and high oral bioavailability of Soanfito in tested animals, with exposure (maximum serum concentration and area under the concentration-time curve [AUC]) being dose proportional.

[0006] The present invention overcomes shortcomings in the art by providing methods for administering Soanfitol to a lactating subject while reducing the likelihood of Soanfitol-induced adverse events in a breastfed infant from the subject. Summary of the Invention

[0007] The present invention relates to methods for developing a method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant from a subject. The present invention further relates to methods for reducing the exposure of a breastfed infant from a subject treated with Soanfitol to Soanfitol.

[0008] Therefore, one aspect of the present invention relates to a method for reducing the exposure of an infant fed with breast milk obtained from a subject treated with Soanfitol, comprising: orally administering Soanfitol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant with breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administering Soanfitol to the subject, thereby reducing the infant's exposure to Soanfitol.

[0009] Another aspect of the present invention relates to a method for reducing the possibility of adverse events caused by Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising: orally administering Soanfitol to the subject at a daily dose of between 37.5 mg and 300 mg; and feeding the infant with breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after Soanfitol is administered to the subject, thereby reducing the possibility of adverse events caused by Soanfitol in the infant. In some embodiments, the daily dose of Soanfitol is 150 mg.

[0010] One aspect of the present invention relates to a method for treating a disorder treatable with Soanfitol in a subject who produces breast milk for feeding an infant, comprising: orally administering Soanfitol to the subject at a daily dose of between 37.5 mg and 300 mg; and reducing exposure to Soanfitol and / or reducing the likelihood of adverse events in an infant breastfed from the subject, comprising feeding the infant breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administering Soanfitol to the subject. The disorder treatable with Soanfitol may be, but is not limited to, narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention deficit / hyperactivity disorder, cognitive impairment, or binge eating disorder.

[0011] Another aspect of the present invention relates to a method of preventing an infant of a nursing mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, such method comprising not feeding said infant breast milk obtained within at least about 3.5 hours (e.g., at least about 4 or 5 hours) of the mother receiving a once daily oral dose of Soanfitol, wherein the T of Soanfitol excreted in said breast milk is less than or equal to 1%. max It is about 1.1 hours.

[0012] Another aspect of the invention relates to a method of reducing the exposure of an infant receiving breast milk from a nursing mother to soanfitol from breast milk, wherein the nursing mother is being treated with a once daily dose of about 37.5 mg to about 300 mg of soanfitol for a disorder amenable to treatment with soanfitol, such method comprising feeding the infant breast milk obtained from the mother at least about 5 hours after administration of soanfitol to the mother, wherein the infant's exposure to soanfitol is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of soanfitol.

[0013] Another aspect of the invention relates to a method of treating excessive daytime sleepiness in a nursing mother, wherein the infant is at risk for an adverse event caused by the mother's excessive daytime sleepiness and the nursing mother desires to breastfeed the infant, the method comprising: (a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant; and (b) providing 37.5 mg once daily (if the excessive daytime sleepiness is associated with obstructive sleep apnea) to the mother who has an ESS total score of 15 or greater and who experiences sleep attacks while caring for the infant. or 75 mg once daily (if excessive daytime sleepiness is associated with narcolepsy), and doubling the dose at intervals of at least 3 days up to 150 mg once daily, wherein the elimination half-life of soanfitol in the plasma of a postpartum or lactating mother is about 5 hours; and (c) feeding the infant breast milk obtained from the mother at least about 3.5 hours (e.g., 4 or 5 hours) after administration of soanfitol to the mother, thereby avoiding exposure of the infant to a maximum concentration of soanfitol in breast milk, wherein the median T of soanfitol excreted in the breast milk is about 5 hours. max It is about 1.1 hours.

[0014] In some embodiments, the method provides an infant daily dose of about 0.3 mg or less of Soanfito. In some embodiments, the method achieves a relative infant dose of less than about 9% of the subject's weight-adjusted dose. In some embodiments, the method achieves a relative infant dose of less than about 5% of the subject's weight-adjusted dose.

[0015] In some embodiments, the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

[0016] In some embodiments, the subject is 1 day to 24 months postpartum or 10 days to 12 months (52 weeks) postpartum.

[0017] In some embodiments, the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, or binge eating disorder.

[0018] In some embodiments, the subject is a female between the ages of 18 and 45.

[0019] In some embodiments, the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

[0020] Provided are methods of treating a disorder amenable to treatment with Soanfito in a subject who is breastfeeding an infant, the methods comprising orally administering Soanfito to the subject at a daily dose of between about 37.5 mg and 300 mg.

[0021] These and other aspects of the invention are set forth in more detail in the description of the invention which follows. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Time courses of the mean sauamfito human milk and plasma concentration-time curves on linear and semi-logarithmic scales.

[0023] Figure 2 Mean cumulative soanfito amount-time curve in breast milk on a linear scale following single-dose administration of soanfito 150 mg tablets. DETAILED DESCRIPTION

[0024] The present invention will now be described in more detail with reference to the accompanying drawings, in which preferred embodiments of the present invention are shown. However, the present invention may be implemented in different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the present invention to those skilled in the art. In addition, any reference cited herein is incorporated by reference in its entirety.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. The terms used in the description of the invention herein are for the purpose of describing specific embodiments only and are not intended to limit the invention. All publications, patent applications, patents, patent publications and other references cited herein are incorporated by reference in their entirety to provide guidance relevant to the sentence and / or paragraph in which the reference appears.

[0026] It is specifically intended that the various features of the invention described herein can be used in any combination, unless the context dictates otherwise.

[0027] Furthermore, the present invention also contemplates that, in some embodiments of the present invention, any feature or combination of features described herein may be excluded or omitted.

[0028] To illustrate, if the specification states that a compound comprises components A, B, and C, it is specifically intended that any one or combination of A, B, or C, alone or in any combination, may be omitted and disclaimed.

[0029] As used in the description of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0030] Also, as used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of any combination when interpreted in the alternative ("or").

[0031] As used herein, the term "about" when referring to a measurable value (such as an amount of a polypeptide, dosage, time, temperature, enzyme activity or other biological activity, etc.) is intended to encompass variations of ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified amount.

[0032] As used herein, the transitional phrase "consisting essentially of (and grammatical variations) should be construed to encompass the recited materials or steps and those materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. Thus, the term "consisting essentially of" as used herein should not be construed as being equivalent to "comprising."

[0033] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of a composition, compound, or agent of the invention that imparts a modulatory effect on a subject suffering from a disorder, disease, or condition, which modulatory effect, for example, can be a beneficial effect, including improving the subject's condition (e.g., one or more symptoms), delaying or reducing disease progression, preventing or delaying the onset of a disorder, and / or changing clinical parameters, diseases, or conditions, etc., as is well known in the art. For example, a therapeutically effective amount or effective amount can refer to an amount of a composition, compound, or agent that improves the subject's condition by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0034] A "pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") refers to a carrier or excipient that can be used to prepare a generally safe and non-toxic pharmaceutical or therapeutic composition, and includes carriers that are acceptable for veterinary and / or human pharmaceutical or therapeutic use. The term "carrier" or "pharmaceutically acceptable carrier" may include, but is not limited to, phosphate-buffered saline solution, water, emulsions (such as oil-in-water or water-in-oil emulsions), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as further described herein.

[0035] The terms "modulate," "modulates," or "modulation" refer to either enhancing (eg, increasing) or inhibiting (eg, decreasing) a specified level or activity.

[0036] The terms "enhance" or "increase" refer to at least about a 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold increase in a specified parameter, and / or can be expressed as an enhancement and / or increase of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more of a specified level and / or activity.

[0037] As used herein, "inhibit" or "reduce" or grammatical variations thereof refer to a decrease or reduction of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more of a specified level or activity. In certain embodiments, the inhibition or reduction results in little or essentially no detectable activity (at most an insignificant amount, e.g., less than about 10% or even 5%).

[0038] As used herein, "treat," "treating," and similar terms in the context of treating a subject refer to providing medical and / or surgical management of the subject. Treatment may include, but is not limited to, administering a medicament or composition (e.g., a pharmaceutical composition) to the subject. Treatment is typically performed in order to alter the course of a disease (a term used to indicate any disease, disorder, syndrome, or undesirable condition that requires or may require treatment) in a manner beneficial to the subject. The effect of treatment may include reversing, alleviating, reducing the severity of a disease or one or more symptoms or manifestations of a disease, delaying its onset, curing, inhibiting its progression, and / or reducing the likelihood of its occurrence or recurrence. Therapeutic agents may be administered to subjects who have a disease or are at an increased risk of developing a disease relative to members of the general population. In some embodiments, therapeutic agents may be administered to subjects who have had a disease but no longer show signs of the disease. For example, the agent may be administered to reduce the likelihood of recurrence of an apparent disease. Therapeutic agents may be administered prophylactically, i.e., before any symptoms or manifestations of the disease develop. "Prophylactic treatment" refers to providing medical and / or surgical management to a subject who has not yet developed a disease or shows no signs of a disease, for example, to reduce the likelihood that the disease will develop, to delay the onset of the disease, or to reduce the severity of the disease if it occurs. The subject may have been identified as being at risk for developing the disease (e.g., at an increased risk relative to the general population) or as having risk factors that increase the likelihood of developing the disease.

[0039] Grammatical variations of "administer," "administration," and "administering" to a subject include any route of introducing or delivering an agent to a subject. Administration can be by any suitable route, including oral, topical, intravenous, subcutaneous, transdermal, transdermal, intramuscular, intra-joint, parenteral, intraarteriolar, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques), and the like. "Concurrent administration," "administered in combination," "administered simultaneously," or "administered simultaneously" as used herein means that the compounds are administered at the same time point, overlapping in time, or one after the other. In the latter case, the two compounds are administered at a time close enough that the observed results are no different from the results achieved when the compounds are administered at the same time point. "Systemic administration" refers to the introduction or delivery of an agent to a subject by a route that introduces or delivers the agent to a wide area of ​​the subject's body (e.g., greater than 50% of the body), such as by entering the circulatory system or lymphatic system. In contrast, "local administration" refers to the introduction or delivery of an agent to a subject by a route that introduces or delivers the agent to the region or region immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, a locally administered agent is easily detectable near the local area of ​​the point of administration, but is not detectable or detectable in negligible amounts in the distal portion of the subject's body. Administration includes self-administration and administration by others.

[0040] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions of the present invention without causing substantial adverse biological effects or interacting in a deleterious manner with any other components of the composition in which it is contained. The material should naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as is well known to those skilled in the art (see, e.g., Remington's Pharmaceutical Science; 21st edition, 2005).

[0041] "In parallel" refers to being close enough in time to produce a combined effect (that is, in parallel can be simultaneously, or it can be two or more events occurring within a short period of time before or after each other). In some embodiments, "in parallel" administration of two or more compounds refers to administering the two compounds close enough in time so that the presence of one compound changes the biological effect of the other compound. The two compounds can be administered in the same or different formulations or administered sequentially. Parallel administration can be performed by mixing the compounds before administration, or administering the compounds in two different formulations, for example, at the same time point but at different anatomical sites, or using different routes of administration.

[0042] As used herein, "bioavailability" refers to the estimated area under the curve, or AUC, of ​​an active drug in the systemic circulation following oral administration with a dosage form as disclosed herein, compared to the AUC of the active drug in the systemic circulation following intravenous administration. The AUC is affected by the extent of drug absorption in the gastrointestinal (GI) tract.

[0043] If the relative mean C of the test product and the reference product max , AUC (0-t) and AUC (0-∞) If the difference is within 80% to 125%, the products are considered "bioequivalent."

[0044] The term "AUC (0-t) ” refers to the area under the plasma concentration curve from time 0 to time t.

[0045] The term "AUC (0-∞) or AUC 0-inf ” is the area under the plasma concentration-time curve from time 0 to infinity.

[0046] “C max ” refers to the maximum milk or plasma concentration of Soanfito.

[0047] “T max ” refers to the time it takes for a given drug to reach maximum milk or plasma concentration.

[0048] “t 1 / 2 ” is the time when the milk and plasma concentrations of the drug decrease by 50% during the terminal elimination phase.

[0049] The milk:plasma ratio is the AUC in milk divided by the AUC in plasma.

[0050] “A 乳汁 ” refers to the amount excreted in breast milk within 72 hours.

[0051] "Vd / F" refers to the apparent volume of distribution in plasma.

[0052] "CL / F" is the apparent oral clearance in plasma.

[0053] AUC0-t is the area under the concentration-time curve from time 0 to time t of the last quantifiable concentration (in milk and plasma).

[0054] "Excessive daytime sleepiness" or "EDS" refers to persistent sleepiness during the daytime at times when an individual would expect to be awake and alert, even after an apparently adequate or even prolonged nighttime sleep. EDS may be the result of a sleep disorder or a symptom of another underlying disorder, such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia. Although the name includes "daytime," it should be understood that sleepiness can occur at other times when the subject should be awake, such as at night or other times, for example, if the subject is working the night shift. It should also be understood that EDS is medically distinct from fatigue and fatigue-related disorders.

[0055] The present invention is based in part on the use of aspirin in lactating subjects with a disorder suitable for treatment with soanfito. (referred to herein as Soanfitol (also referred to as (R)-2-amino-3-phenylpropylcarbamate (APC) hydrochloride, and formerly known as JZP-110, ADX-N05, R228060, and YKP10A)), while reducing the likelihood of adverse effects in a breastfed infant of the subject. Soanfitol is FDA-approved for administration at doses equivalent to 37.5 mg, 75 mg, and 150 mg of APC (corresponding to 44.7 mg, 89.3 mg, and 178.5 mg of APC hydrochloride, respectively). There are challenges in administering Soanfitol to subjects who express breast milk. In nonclinical studies in rats, Soanfitol was detected in breast milk, and Soanfitol milk concentrations were higher than Soanfitol plasma concentrations. It is desirable to reduce or minimize any adverse effects caused by the daily dose received by breastfed infants from subjects treated with Soanfitol. Additionally, methods are desired to determine the safety and tolerability of Soanfito in lactating subjects.

[0056] Therefore, one aspect of the present invention relates to a method for reducing the exposure of an infant fed with breast milk obtained from a subject treated with Soanfitol, comprising orally administering Soanfitol to the subject at a daily dose of about 37.5 mg to about 300 mg; and feeding the infant breast milk from the subject for at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after administering Soanfitol to the subject, thereby reducing the infant's exposure to Soanfitol.

[0057] One aspect of the present invention includes a method for reducing the possibility of adverse events caused by Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising orally administering Soanfitol to the subject at a daily dose of between 37.5 mg and 300 mg; and feeding the infant with breast milk from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after Soanfitol is administered to the subject, thereby reducing the possibility of adverse events caused by Soanfitol in the infant. In one embodiment, the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

[0058] Another aspect of the present invention relates to a method of preventing an infant of a nursing mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, such method comprising not feeding the infant breast milk obtained within at least about 3.5 hours (e.g., at least about 4 or 5 hours) of the mother receiving a once-daily oral dose of Soanfitol, wherein the median T of Soanfitol excreted in the breast milk is max is about 1.1 hours. In clinical studies, T max The range is 1 hour to 3 hours. Therefore, waiting at least 3.5 hours after administering Soanfito ensures that T is avoided even for abnormal subjects. max .

[0059] Another aspect of the present invention relates to a method for reducing the exposure of an infant to Soanfitol from breast milk who is receiving breast milk from a nursing mother who is being treated with a once-daily dose of about 37.5 mg to about 300 mg of Soanfitol for a disorder suitable for treatment with Soanfitol, the method comprising feeding the infant breast milk obtained from the mother at least about 5 hours (e.g., at least 6, 7, 8, 9, or 10 hours) after Soanfitol is administered to the mother, wherein the infant's exposure to Soanfitol is reduced by at least about 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%) compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after Soanfitol administration. In some embodiments, the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose. In some embodiments, the once daily dose of Soanfituo is 150 mg, and the daily amount of Soanfituo passed to the infant through breast milk is about 0.3 mg or less. In some embodiments, the once daily dose of Soanfituo is 75 mg, and the daily amount of Soanfituo passed to the infant through breast milk is about 0.15 mg or less. In some embodiments, breast milk is obtained from the mother at least about 10 hours (e.g., about 2 half-lives) after Soanfituo is administered to the mother, and the infant's exposure to Soanfituo is reduced by at least about 75% compared to the exposure that would result from breast milk obtained from the mother less than 5 hours after administering Soanfituo. In some embodiments, the relative infant dose obtained is about 1% or less of the mother's weight-adjusted dose.

[0060] One aspect of the present invention relates to a method for treating a disorder that can be treated with Soanfitol in a subject who produces breast milk for feeding an infant, comprising orally administering Soanfitol to the subject at a daily dose of between 37.5 mg and 300 mg; and reducing exposure to Soanfitol and / or reducing the likelihood of adverse events in a breastfed infant from the subject, comprising feeding the infant breast milk obtained from the subject at least about 2 hours (e.g., at least about 3, 4, or 5 hours) after Soanfitol is administered to the subject. In one embodiment, the method reduces Soanfitol in the infant, and the infant does not experience agitation, insomnia, anorexia, or decreased weight gain caused by Soanfitol exposure. In one embodiment, the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

[0061] "Disorder suitable for treatment with Suoanfeituo" or "disorder treatable with Suoanfeituo" refers to any disorder in which the administration of Suoanfeituo to a subject results in one or more symptoms of the subject's disorder being treated. Example disorders suitable for treatment with Suoanfeituo include narcolepsy, cataplexy, excessive daytime sleepiness, obstructive sleep apnea, shift work disorder, drug addiction, sexual dysfunction, fatigue, fibromyalgia, attention deficit hyperactivity disorder (ADHD), cognitive impairment and / or cognitive dysfunction, Parkinson's disease, restless legs syndrome, depression, bipolar disorder, obesity, or binge eating disorder. In some embodiments, the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease. In some embodiments, the disorder suitable for treatment with Suoanfeituo includes narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention deficit / hyperactivity disorder, or binge eating disorder. In some embodiments, Suoanfeituo is administered to improve wakefulness. See, e.g., U.S. Patent Nos. 8,232,315, 8,440,715, 8,552,060, 8,623,913, 8,729,120, 8,741,950, 8,895,609, 8,927,602, 9,226,910, and 9,359,290; and U.S. Publication Nos. 2012 / 0004300 and 2015 / 0018414. All of the above patents and applications are hereby incorporated by reference in their entirety for all purposes.

[0062] "Excessive daytime sleepiness" or "EDS" refers to persistent sleepiness during the daytime at times when an individual would expect to be awake and alert, even after an apparently adequate or even prolonged nighttime sleep. EDS may be the result of a sleep disorder or a symptom of another underlying disorder, such as narcolepsy, sleep apnea, circadian rhythm sleep disorder, or idiopathic hypersomnia. Although the name includes "daytime," it should be understood that sleepiness can occur at other times when the subject should be awake, such as at night or other times, for example, if the subject is working the night shift. It should also be understood that EDS is medically distinct from fatigue and fatigue-related disorders.

[0063] In some embodiments, the cause of EDS can be, but is not limited to, central nervous system (CNS) pathological abnormalities, stroke, narcolepsy, idiopathic CNS hypersomnia; sleep deprivation, sleep apnea, obstructive sleep apnea, insufficient sleep at night, chronic pain, acute pain, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, major depression, bipolar disorder, myocardial ischemia; imbalance between the body's circadian pacemaker and the environment, jet lag, shift work disorder, or sedative medications.

[0064] In certain embodiments, the structure of Soanfito as Formula I is given below:

[0065]

[0066] Methods for preparing Soanfito and related compounds can be found in U.S. Patent Nos. 10,829,443, 5,955,499, 5,705,640, 6,140,532, and 5,756,817. All of the above patents and applications are hereby incorporated by reference in their entirety for all purposes.

[0067] In one embodiment, the method described in detail herein provides that the infant of the breastfeeding of the experimenter to which Suo An Fei Tuo is applied does not experience adverse events, for example, the restlessness, insomnia, anorexia or weight gain caused by Suo An Fei Tuo exposure are reduced. The restlessness, insomnia, anorexia or weight gain of the infant can be monitored. For example, weight loss, weight gain can be reduced, feeding frequency can be reduced or intake can be reduced, and the volume of milk taken can be monitored and / or detected. The increase of the restlessness and / or insomnia of the infant can also be monitored, including the reduction of sleeping time and / or the reduction of the time of falling asleep and keeping sleep, to determine the change of the infant. In some embodiments, 3 or more hours after applying Suo An Fei Tuo dosage and after starting to use the breast-fed infant from the experimenter, for example, 3 hours, 4, hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours or more after applying Suo An Fei Tuo dosage, the change of the infant is monitored. Any changes experienced by the infant (e.g., restlessness, insomnia, anorexia, or decreased weight gain) can be monitored over the period of time that the subject is administered Soanfitol, which can be measured in days, weeks, or months, with monitoring occurring at any interval within that period, including hourly, daily, weekly, monthly, or any time range therein.

[0068] In one embodiment, the method provides an infant daily dose of about 0.4 mg or less of Soanfitol, e.g., about 0.39 mg, about 0.38 mg, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.335 mg, about 0.33 mg, about 0.32 mg, about 0.21 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.2 In some embodiments, the daily dose of about 150mg of Suoanfeituo is orally administered to a subject, and due to the waiting period after administration, the daily dose of Suoanfeituo is reduced to about 0.3mg or less. In some embodiments, a once-daily dose of about 75 mg of Soanfitol is orally administered to a subject, and due to a waiting period after administration, the infant daily dose of Soanfitol is reduced to about 0.15 mg or less. In some embodiments, a once-daily dose of about 37.5 mg of Soanfitol is orally administered to a subject, and due to a waiting period after administration, the infant daily dose of Soanfitol is reduced to about 0.08 mg or less.

[0069] In one embodiment, the method provides an infant daily dose of soanfitol of about 0.2 mg / kg (based on a nominal infant weight of 6 kg) or less, e.g., about 0.19 mg / kg, about 0.18 mg / kg, about 0.17 mg / kg, about 0.16 mg / kg, about 0.15 mg / kg, about 0.14 mg / kg, about 0.13 mg / kg, about 0.12 mg / kg, about 0.11 mg / kg, about 0.10 mg / kg, about 0.09 mg / kg, about 0.08 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, about 0.02 mg / kg, about 0.01 mg / kg or less.

[0070] In one embodiment, the method provides a cumulative median infant dose of Soanfito of about 0.7 mg or less within 72 hours after a single dose, e.g., about 0.69 mg, about 0.68 mg, about 0.67 mg, about 0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg, about 0.61 mg, about 0.60 mg, about 0.59 mg, about 0.58 mg, about 0.57 mg, about 0.56 mg, about 0.55 mg, about 0.54 mg, about 0.53 mg, about 0.52 mg, about 0.51 mg, about 0.50 mg, about 0.49 mg, about 0.48 mg, about 0.47 mg, about 0.46 mg, about 0.45 mg, about 0.44 mg, about 0.43 mg, about 0. .42 mg, about 0.41 mg, about 0.40 mg, about 0.39 mg, about 0.38 mg, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.355 mg, about 0.33 mg, about 0.32 mg, about 0.31 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.23 mg, about 0.22 mg, about 0.21 mg, about 0.20 mg, about 0.19 mg, about 0.18 mg, about 0.17 mg, about 0.16 mg, about 0.15 mg, about 0.14 mg, about 0.13 mg, about 0.12 mg, about 0.11 mg, about 0.10 mg or less.

[0071] In some embodiments, the method provides a cumulative median infant dose of Soanfitol after 8 hours of a single dose of about 75%-80%, for example, about 75%, 76%, 77%, 78%, 79% or 80% of the total amount excreted within 72 hours. In some embodiments, the method provides a cumulative median infant dose of Soanfitol after 24 hours of a single dose of about 95%-100%, for example, about 95%, 96%, 97%, 98%, 99% or 100% of the total amount excreted within 72 hours.

[0072] In some embodiments, breast milk for feeding an infant is expressed or produced from the subject 2 or more hours, 2.5 or more hours, 3 or more hours, 3.5 or more hours, 4 or more hours, 4.5 or more hours, or 5 or more hours after the subject is administered a dose of Soanfitol, for example, at 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours or more. In some embodiments, breast milk for infant feeding produced from a subject in the methods detailed herein occurs at about the mean elimination half-life of Soanfitol or later, i.e., about 5 hours after administration of Soanfitol. In some embodiments, breast milk for infant feeding produced from a subject in the methods detailed herein occurs at the median T of Soanfitol. max In some embodiments, the infant is breastfed 3 or more hours, 4 or more hours, or 5 or more hours after the subject is administered a dose of Suoanfeituo. In some embodiments, breast milk is obtained from the subject for feeding the infant 3 or more hours, 4 or more hours, or 5 or more hours after the subject is administered a dose of Suoanfeituo.

[0073] In some embodiments, the subject is not breastfed during the waiting period (e.g., 2 or more hours).In other embodiments, the breast milk produced during the waiting period is expressed and not fed to the infant, e.g., wherein the expressed milk is discarded.

[0074] In some embodiments, the methods achieve less than about 10%, less than about 9.5%, less than about 9%, less than about 8.5%, less than about 8%, less than about 7.5%, less than about 7%, less than about 6.5%, less than about 6%, less than about 5.5%, less than about 5%, less than about 4.9%, less than about 4.8%, less than about 4.7%, less than about 4.6%, less than about 4.5%, less than about 4.4%, less than about 4.3%, less than about 4.2%, less than about 4.1%, less than about 4.0%, less than about 3.9%, less than about 3.8%, less than about 3.7%, less than about 3.6%, less than about 3.5%, less than about 3. 4%, less than about 3.3%, less than about 3.2%, less than about 3.1%, less than about 3.0%, less than about 2.9%, less than about 2.8%, less than about 2.7%, less than about 2.6%, less than about 2.5%, less than about 2.4%, less than about 2.3%, less than about 2.2%, less than about 2.1%, less than about 2.0%, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, less than about 1.0% of the relative infant dose - the percentage of the subject's weight-adjusted dose excreted in breast milk over 24 hours.

[0075] In some embodiments, the cumulative median amount of Soanfitol delivered to breastfed infants produced by subjects treated with Soanfitol according to the methods disclosed herein over a 72-hour period is less than about 0.70 mg, about 0.69 mg, about 0.68 mg, about 0.67 mg, about 0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg, about 0.61 mg, about 0.60 mg, about 0.59 mg, or about 0.66 mg. mg, about 0.58 mg, about 0.57 mg, about 0.56 mg, about 0.55 mg, about 0.54 mg, about 0.53 mg, about 0.52 mg, about 0.51 mg, about 0.50 mg, about 0.49 mg, about 0.48 mg, about 0.47 mg, about 0.46 mg, about 0.45 mg, about 0.44 mg, about 0.43 mg, about 0.42 mg, about 0.41 mg, about 0.40 mg, about 0.3 9mg, about 0.38mg, about 0.37mg, about 0.36mg, about 0.35mg, about 0.34mg, about 0.335mg, about 0.33mg, about 0.32mg, about 0.31mg, about 0.30mg, about 0.29mg, about 0.28mg, about 0.27mg, about 0.26mg, about 0.25mg, about 0.24mg, about 0.23mg, about 0.22mg, about 0.21mg, about 0.20 mg, about 0.19 mg, about 0.18 mg, about 0.17 mg, about 0.16 mg, about 0.15 mg, about 0.14 mg, about 0.13 mg, about 0.12 mg, about 0.11 mg, about 0.10 mg, about 0.09 mg, about 0.08 mg, about 0.07 mg, about 0.06 mg, about 0.05 mg, about 0.04 mg, about 0.03 mg, about 0.02 mg or about 0.01 mg.

[0076] In some embodiments, the cumulative median amount of Soanfitol delivered to a breastfed infant produced by a subject treated with Soanfitol according to the methods disclosed herein over a 24-hour period is less than about 0.70 mg, about 0.69 mg, about 0.68 mg, about 0.67 mg, about 0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg, about 0.61 mg, about 0.60 mg, about 0. 59mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg, about 0.41mg, about 0.40mg , about 0.39 mg, about 0.38 mg, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.33 mg, about 0.32 mg, about 0.31 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.23 mg, about 0.22 mg, about 0.21 mg, about 0. 07 mg, about 0.06 mg, about 0.05 mg, about 0.04 mg, about 0.03 mg, about 0.02 mg or about 0.01 mg.

[0077] In some embodiments, the cumulative median amount of Soanfitol delivered to a breastfed infant produced by a subject treated with Soanfitol according to the methods disclosed herein over an 8-hour period is less than about 0.70 mg, about 0.69 mg, about 0.68 mg, about 0.67 mg, about 0.66 mg, about 0.65 mg, about 0.64 mg, about 0.63 mg, about 0.62 mg, about 0.61 mg, about 0.60 mg, about 0.5 9mg, about 0.58mg, about 0.57mg, about 0.56mg, about 0.55mg, about 0.54mg, about 0.53mg, about 0.52mg, about 0.51mg, about 0.50mg, about 0.49mg, about 0.48mg, about 0.47mg, about 0.46mg, about 0.45mg, about 0.44mg, about 0.43mg, about 0.42mg, about 0.41mg, about 0.40mg, about 0.39 mg, about 0.38 mg, about 0.37 mg, about 0.36 mg, about 0.35 mg, about 0.34 mg, about 0.33 mg, about 0.32 mg, about 0.31 mg, about 0.30 mg, about 0.29 mg, about 0.28 mg, about 0.27 mg, about 0.26 mg, about 0.25 mg, about 0.24 mg, about 0.23 mg, about 0.22 mg, about 0.21 mg, about 0.2 0 mg, about 0.19 mg, about 0.18 mg, about 0.17 mg, about 0.16 mg, about 0.15 mg, about 0.14 mg, about 0.13 mg, about 0.12 mg, about 0.11 mg, about 0.10 mg, about 0.09 mg, about 0.08 mg, about 0.07 mg, about 0.06 mg, about 0.05 mg, about 0.04 mg, about 0.03 mg, about 0.02 mg or about 0.01 mg.

[0078] A daily dose of about 1 to about 2000 mg of Soanfeituo or a pharmaceutically acceptable salt thereof can be administered to achieve the therapeutic results disclosed herein. For example, a daily dose of about 1-1000 mg (e.g., about 20-500 mg) is administered in a single dose or divided doses. In some embodiments, the daily dose can be about 0.01 to about 150 mg / kg body weight, for example, about 0.2 to about 18 mg / kg body weight. In some embodiments, the dosage contains about 1 mg to about 1000 mg of the drug or any range or value therein, for example, about 10 mg to about 500 mg, for example, about 37.5 mg, about 75 mg, about 150 mg or about 300 mg. For example, in some such embodiments, the total amount of the drug can be selected from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300 or any range therein.

[0079] In one embodiment of the invention, Suo Anfeituo is administered to the subject as needed to treat the disorder. The compound can be administered continuously or intermittently. In one embodiment, the compound is administered to the subject more than once a day, for example, 2, 3 or 4 times a day, or every 1, 2, 3, 4, 5, 6 or 7 days. In another embodiment, the compound is administered to the subject no more than once a week, for example, no more than once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months or longer. In another embodiment, two or more different schedules are used to administer the compound, for example, initially more frequently (for example, gradually increasing to a certain level, for example, once a day or more), and then less frequently (for example, once a week or less). In other embodiments, the compound can be administered by any discontinuous administration scheme. In one example, the compound can be administered no more than every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days or every ten days or longer. The administration can last for one week, two weeks, three weeks or four weeks or one month, two months or three months or longer. Optionally, after a period of rest, the compound may be administered on the same or different schedule. The rest period may be one week, two weeks, three weeks, or four weeks or longer, depending on the pharmacodynamic effects of the compound on the subject. In another embodiment, the compound may be administered to gradually increase to a certain level, then maintained at a constant level, and then gradually reduced in dose.

[0080] In one aspect of the invention, Soanfito is delivered to the subject in parallel with another therapeutic agent. The additional therapeutic agent can be delivered in the same composition as the compound, or in a separate composition. The additional therapeutic agent can be delivered to the subject on a different schedule or by a different route than the compound. The additional therapeutic agent can be any agent that provides a benefit to the subject. Additional agents include, but are not limited to, stimulants, antipsychotics, antidepressants, agents for neurological disorders, and chemotherapeutic agents. A therapeutic agent that can be administered during the same time period is Commercially sold by Jazz Pharmaceuticals for the treatment of narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0081] The present invention is used in research and veterinary and medical applications. Suitable subjects are typically mammalian subjects. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), etc. Human subjects include neonates, infants, teenagers, adults, and elderly subjects. In some embodiments, the subject is a postpartum subject. In some embodiments, the subject is a woman between the ages of 18 and 45 years old.

[0082] Suitable subjects are typically mammalian subjects in the lactation period. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice) etc. The human subject can be a lactation individual that often or regularly breastfeeds an infant. In some embodiments, the human subject is a woman. The women's age can be between approximately 18 and 45 years old. The term "breastfeeding" (also known as chest feeding or its grammatical changes) refers to individual breast milk being delivered directly to the infant, using a device to extract breast milk from the individual and subsequently delivering it to the infant, using a device to extract breast milk from the individual and storing breast milk for a period of time and subsequently delivering the stored breast milk to the infant or its combination.

[0083] The subject of the present disclosure can be in the lactation period, for example, an individual who is lactating (e.g., producing breast milk), nursing, or breastfeeding. The subject can be in the lactation period after pregnancy (i.e., postpartum) or by induced lactation (e.g., with metoclopramide, oral contraceptives, herbal remedies, by pump stimulation, or any combination thereof).

[0084] In some embodiments, the subject is between 1 day and 24 months postpartum, between about 1 day and 12 months postpartum, between about 10 days and 12 months (52 weeks) postpartum, or between about 15 weeks to about 37 weeks postpartum. In some embodiments, the subject expresses mature milk, which typically occurs between about 10 and about 30 days postpartum (e.g., about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days), or about 10 to about 20 days postpartum, or about 10 to about 20 days after initiation of milk expression in induced lactation. Infancy begins at birth and ends around the age of 2 years; therefore, the period of infancy while breastfeeding includes the breastfeeding period.

[0085] The subject can be a subject "in need" of the method of the present invention, for example, a subject in need of the therapeutic effect of the method of the present invention. For example, the subject can be a subject experiencing a disorder suitable for treatment with Suoanfeituo, a subject suspected of having a disorder suitable for treatment with Suoanfeituo, and / or a subject expected to experience a disorder suitable for treatment with Suoanfeituo, and the methods and compositions of the present invention are used for therapeutic treatment and / or prophylactic treatment.

[0086] In some embodiments, the subject is a mother whose disease or disorder places her infant at risk for an adverse event due to the maternal condition (e.g., she falls asleep while caring for her infant), and the mother desires to breastfeed. Surveys show that at least 60% of women with narcolepsy report having difficulty caring for their infants due to their symptoms and worry that their disease will impair their ability to care for their infants.

[0087] Thus, one aspect of the present invention relates to a method for treating excessive daytime sleepiness in a nursing mother whose infant is at risk for an adverse event caused by the mother's excessive daytime sleepiness and who desires to breastfeed the infant, the method comprising: (a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant; (b) providing 37.5 mg once daily (if the excessive daytime sleepiness is associated with obstructive sleep apnea) or 7 mg once daily to the mother who has an ESS total score of 15 or greater and experiences sleep attacks while caring for the infant. 5 mg once daily (if excessive daytime sleepiness is associated with narcolepsy) and doubling the dose at intervals of at least 3 days up to 150 mg once daily, wherein the elimination half-life of soanfitol in the plasma of a postpartum or lactating mother is about 5 hours; and (c) feeding the infant breast milk obtained from the mother at least about 3.5 hours (e.g., 4 or 5 hours) after administration of soanfitol to the mother, thereby avoiding exposure of the infant to a maximum concentration of soanfitol in breast milk, wherein the median T of soanfitol excreted in the breast milk is about 5 hours. max It is about 1.1 hours.

[0088] This approach selects subjects suitable for treatment based on disease severity, interference with infant care, and the mother's desire to provide the infant with the developmental and health benefits of breastfeeding.

[0089] The ESS is a subjective sleepiness test well known in the art and is routinely used to measure a subject's sleepiness level. The scale is intended to measure daytime sleepiness by using a short questionnaire that requires the subject to rate his or her probability of falling asleep on an increasing probability scale from 0 to 3 for eight different situations that most people encounter in their daily lives. The scores of the eight questions are added together to obtain a single number that estimates the subject's average sleep tendency (ASP). Numbers within the range of 0-10 are considered normal, while 11-12 represent mild excessive sleepiness, 13-15 represent moderate excessive sleepiness, and 16 or higher represent severe excessive sleepiness. Narcolepsy patients have an average score of about 17. Obstructive sleep apnea (OSA) patients who suffer from excessive sleepiness have an average score of about 15.

[0090] As used herein, "sleep attacks" refer to strong urges to sleep, typically followed by a period of sleep in which one has no control over when sleep falls in. These periods can last from a few seconds to half an hour.

[0091] In some embodiments, the lactating mother experiences a decrease in ESS total score of 5 or more (eg, 6, 7, 8, 9, or 10 or more).

[0092] In some embodiments, the nursing mother experiences a reduction in the frequency of sleep episodes while holding, feeding, nursing, or otherwise caring for the infant. The reduction in frequency can be at least about 10%, 20%, 30%, 40%, or 50% compared to untreated mothers.

[0093] In some embodiments, the nursing mother experiences a reduction in automatic movements (movements of a body part, such as movements of her hands during sleep) while caring for her infant. The reduction in automatic movements can be at least about 10%, 20%, 30%, 40%, or 50% compared to untreated mothers.

[0094] Having described the present invention, it will be explained in more detail in the following examples, which are included herein for illustrative purposes only and are not intended to limit the present invention.

[0095] Example

[0096] Example 1. Phase 4 clinical trial in breastfeeding subjects

[0097] A Phase 4, open-label, single-dose study was conducted to evaluate the pharmacokinetics (PK) of Soanfito in breast milk and plasma following oral administration of 150 mg Soanfito tablets to healthy postpartum women.

[0098] A single oral dose of 150 mg of SUNOSI was administered to six healthy lactating adult women between 15 and 37 weeks postpartum. SUNOSI is excreted in breast milk with a milk to plasma AUC ratio of approximately 2:1. The median T of SUNOSI in breast milk is 2. max The average elimination half-life of SUNOSI in breast milk is approximately 1.1 hours, and the average elimination half-life in breast milk is approximately 5.0 hours. The estimated average amount transferred to the infant over a 24-hour period is 0.59 mg, which is approximately 4.0% of the maternal dose adjusted for body weight. Data from lactation studies indicate that SUNOSI is transferred into the breast milk of nursing mothers, with a relative infant dose (RID) of approximately 4% of the maternal weight-adjusted dose. No data were provided to evaluate the effects of SUNOSI on breastfed infants or milk production. The developmental and health benefits of breastfeeding, as well as the mother's clinical need for SUNOSI, and any potential adverse effects of SUNOSI or underlying maternal conditions on the breastfed child should be considered. Breastfed infants should be monitored for adverse reactions such as restlessness, insomnia, anorexia, and decreased weight gain.

[0099] Suoanfeito has a short systemic elimination half-life of 5.0 to 7.6 hours, and the estimated accumulation ratio with once-daily dosing is 1.06, slightly higher than 1, indicating that there is essentially no accumulation with repeated dosing. Therefore, a single therapeutic dose of Suoanfeito was administered in this study. Since the objectives of this study were to evaluate the PK of Suoanfeito in breast milk and plasma and to estimate the daily drug dose received by infants through breast milk, the highest approved therapeutic dose of Suoanfeito, 150 mg, was administered.

[0100] The subjects were between 10 days and 52 weeks postpartum. The lower limit of 10 days postpartum represents the time after which mature milk is produced (US FDA 2019). The upper limit of 52 weeks postpartum was chosen based on a prospective study that showed that fat, total solids, and "energy" (kcal / dL) were statistically increased in breast milk collected 12 to 18 months postpartum (N=25) compared with breast milk collected 1 to 12 months postpartum (N=35) (Czosnykowska Lukacka 2018). In addition, there is little data on the nutritional composition of breast milk >12 months postpartum (Wu 2018). The study included frequent collection of breast milk samples during the 72-hour period after dosing to enable the detection of soanfitol that may be present in breast milk. Plasma concentrations of soanfitol were also evaluated during the same time period to assess the potential accumulation of soanfitol in breast milk relative to plasma.

[0101] Subjects were instructed not to breastfeed their infants within 72 hours after the dose.Based on the short half-life of the drug, this time period (10× half-life) was expected to be of sufficient duration to allow for complete elimination of Soanfito from both the systemic circulation and breast milk.

[0102] Pharmacokinetic results

[0103] All subjects in the PK population were included in the PK analysis. The pharmacokinetic population was defined as all subjects who received study drug and provided post-dose breast milk or plasma PK data for at least one collection interval or time point. Subjects 1003, 1004, and 1007 had multiple documented protocol deviations in terms of the timing of food consumption; however, these deviations were unlikely to have affected the PK of Soanfito, and these subjects were included in the descriptive statistics or PK parameter analysis. In addition, the PK of Soanfito in fed and fasted subjects met the bioequivalence criteria, indicating that Soanfito can be taken regardless of food intake.

[0104] Figure 1 Mean plasma and breast milk sulphafenatide concentration-time profiles are shown in . Figure 1 Shown is the time course of mean plasma and breast milk Soanfitol concentrations on day 1 following a single dose of Soanfitol 150 mg tablets administered 2 hours after a light breakfast in the morning. After reaching maximum Soanfitol concentrations approximately 1.00 to 3.00 hours after oral administration, plasma and breast milk exposures followed parallel monoexponential declines. Soanfitol concentrations in breast milk were approximately twice as high as plasma concentrations.

[0105] Figure 2 The mean cumulative breast milk soanfidobacterium dose-time curves are shown in . Figure 2 The mean cumulative breast milk excretion of Soanfetol after a single dose of Soanfetol 150 mg tablets 2 hours after a light breakfast in the morning is shown over time. The arithmetic mean ± SD amount excreted in breast milk over 72 hours was 0.6880 ± 0.4672 mg. However, almost complete excretion was observed within 24 hours of dosing.

[0106] No subject had an adjusted Rsq value < 0.700 or %AUCex > 20%, so both λ_z and AUC0-inf related parameters were considered reliable and included in the descriptive statistics.

[0107] Table 1 summarizes the plasma and human milk PK parameters of Soanfito following single-dose administration.

[0108] The exposure of Soanfito in breast milk was approximately twice as high as that in plasma, with a geometric mean C max 1861 vs. 892.5 ng / mL, AUC 0-twere 12770 versus 6236 h*ng / mL, and AUC 0-inf The geometric mean milk:plasma ratio was 2.047.

[0109] Plasma Soanfito max The duration of gestational age was similar to that of breast milk (ranging from 0.98 to 3.02 hours, median 1.25 hours) (range, median 1.00 to 3.00 hours, median 1.12 hours).

[0110] The geometric mean Soanfito t between plasma (4.751 hours) and breast milk (4.869 hours) 1 / 2 In addition, the geometric mean plasma CL / F of Soanfito was 23.66 L / h, and V z / F is 162.2L. Geometric mean A 乳汁 The daily and relative infant doses were 0.5856 mg and 4.030%, respectively.

[0111] Table 1: Summary of the pharmacokinetic parameters of Soanfito in plasma and breast milk (pharmacokinetic population)

[0112]

[0113] NC = Not Calculated.

[0114] Note: CV% is based on the arithmetic mean.

[0115] [a] Median value (min, max).

[0116] Pharmacokinetic conclusions

[0117] Soanfetol in both plasma and breast milk max After reaching the maximum concentration of serotonin, plasma and breast milk exposures followed a parallel monoexponential decline. max The AUC and AUC of the breast milk samples were twice as high as those in plasma. In addition, the geometric mean milk: plasma ratio was 2.047. 1 / 2 This study looked specifically at postpartum women, similar to current This is a very different population than the population studied reported in the pharmacokinetic section of the label, which was non-postpartum healthy male and female patients. The label reports that the oral bioavailability of Soanfito is approximately 95% under fasting conditions in healthy, non-postpartum male and female patients, with peak plasma concentrations of Soanfito occurring at a median T of 2 hours post-dose. max(range 1.25 to 3.0 hours). In fact, although the median T reported for healthy male and female patients in non-postpartum patients is reported in the label max 2 hours, but in this lactation study T max is 1 hour. Similarly, for The apparent mean elimination plasma half-life in non-postpartum healthy male and female patients on label was 7.1 hours, compared to 4.8 hours in plasma and 4.95 hours in breast milk in this lactation study.

[0118] CL / F and V determined only for plasma Soanfito z / F. The arithmetic mean of CL / F is 24.40L / h, and V z / F is 168.9 L. Only for breast milk, A is determined 乳汁 , infant daily dose and relative infant dose. A 乳汁 The arithmetic mean was 0.6880 mg, the infant daily dose was 0.6927 mg, and the relative infant dose was 4.602%.

[0119] Safety results

[0120] Adverse events: An overall summary of treatment-emergent adverse events (TEAEs) is summarized in Table 2. A total of 3 subjects (50%) had at least 1 AE; a total of 2 subjects (33.3%) had a TEAE related to study drug, and 1 subject (16.7%) had a TEAE not related to study drug. Mild TEAEs were reported in 2 subjects (33.3%), and moderate TEAEs were reported in 1 subject (16.7%). No SAEs were reported during the study. No subjects discontinued due to TEAEs.

[0121] Table 2: Overall Summary of Treatment-Emergent Adverse Events (Safety Population)

[0122]

[0123]

[0124] AE = adverse event; N = number of exposed subjects; SAE = serious adverse event.

[0125] Note: The percentage is based on N

[0126] aSubjects reporting adverse events in more than one category were counted only once for that category.

[0127] Of the 3 subjects who reported TEAEs, 1 subject had dizziness and headache (SOC: Nervous system disorders), 1 subject had agitation (SOC: Psychiatric disorders), and 1 subject had a headache event (SOC: Nervous system disorders) (Table 3). A total of 4 TEAEs were reported, of which 3 TEAEs (dizziness, headache, and agitation) were mild in intensity and 1 TEAE (headache) was moderate in intensity. All 3 mild TEAEs were related to study drug, and the moderate TEAE was not related to study drug. All TEAEs resolved.

[0128] Table 3: Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term (Safety Population)

[0129]

[0130] N = number of exposed subjects.

[0131] Note: Percentages are based on N.

[0132] Subjects with multiple adverse events within a major system organ class were counted only once.

[0133] Subjects with multiple AEs were counted only once in the AE category.

[0134] System organ classes are presented alphabetically; preferred terms are presented alphabetically within system organ classes. Adverse events are coded using the MedDRA coding dictionary MedDRA180 Mixed.

[0135] Vital signs: There were no major changes in vital sign parameters from baseline to 2 and 4 hours on Day 1, Day 2, Day 3, and Day 4. A summary of clinically significant vital signs at any post-baseline visit is summarized in Table 4.

[0136] Table 4: Summary of Clinically Significant Vital Signs at Any Post-Baseline Visit / Time Point (Safety Population)

[0137]

[0138] N = number of exposed subjects.

[0139] Note: Percentages are based on N.

[0140] Baseline was defined as the last nonmissing measurement taken before dosing. All post-baseline assessments (including unplanned assessments) were considered for this summary.

[0141] There were no major changes in ECG parameters from baseline to pre-dose and 2 hours on Day 1, Day 2, Day 3, and Day 4. No abnormal, clinically significant ECG findings were reported.

[0142] A summary of clinically significant ECG findings at any post-baseline visit is summarized in Table 5.

[0143] Table 5: Summary of Clinically Significant Electrocardiograms at Any Post-Baseline Visit / Time Point (Safety Population)

[0144]

[0145] N = number of exposed subjects.

[0146] Note: Percentages are based on N.

[0147] Baseline was defined as the last nonmissing measurement taken before dosing. All post-baseline assessments (including unplanned assessments) were considered for this summary.

[0148] According to the Columbia-Classification Algorithm for Suicide Assessment, none of the subjects reported any suicidal ideation or events.

[0149] Safety Conclusion

[0150] Overall, 6 subjects were enrolled in the safety analysis and were treated with a single oral dose of Soanfito, which was safe and well tolerated.

[0151] Of the 6 subjects, 3 (50%) had at least 1 AE. Of the 3 subjects who reported TEAEs: 1 subject had dizziness and headache (SOC: Nervous system disorders), both of mild intensity and related to study drug; 1 subject had agitation (SOC: Psychiatric disorders) of mild intensity and related to study drug; 1 subject had a headache event (SOC: Nervous system disorders) of moderate intensity and not related to study drug. No SAEs, deaths, or other major AEs were reported in the study. No subjects discontinued due to TEAEs. No subjects had abnormal, clinically significant laboratory findings. There were no major changes in vital signs from baseline to 2 hours and 4 hours on Day 1, Day 2, Day 3, and Day 4, and there were no major changes in ECG parameters from baseline to pre-dose and 2 hours on Day 1, Day 2, Day 3, and Day 4. No subjects reported any suicidal ideation or events according to the Columbia Suicide Assessment Classification Algorithm.

[0152] discuss

[0153] This study was a Phase 4, open-label, single-dose study evaluating the PK of Soanfito in breast milk and plasma following oral administration of 150 mg Soanfito tablets in healthy postpartum women. A total of six subjects were enrolled and included in both PK and safety analyses. All six subjects completed the study. No premature discontinuations were reported during the study.

[0154] The primary objective (PK) of the study was to evaluate the PK of Soanfito in plasma and breast milk following a single oral dose of Soanfito 150 mg tablets 2 hours after completing a light breakfast in the morning. The exposure of Soanfito in breast milk was approximately 2 times higher than that in plasma, with a geometric mean C max 1861 vs. 892.5 ng / mL, AUC 0-t were 12770 versus 6236 h*ng / mL, and AUC 0-inf The geometric mean milk: plasma ratio was 2.047. max The geometric mean serotonin duration between plasma (4.751 h) and breast milk (4.869 h) was similar to that of breast milk (1.00 to 3.00 h, median 1.12 h). 1 / 2 In addition, the geometric mean plasma CL / F of Soanfito was 23.66 L / h, and V z / F is 162.2L. Geometric mean A 乳汁 The daily and relative infant doses were 0.5856 mg and 4.030%, respectively.

[0155] The secondary objective of the study was to evaluate the safety and tolerability of Soanfito in healthy postpartum women. Overall, the study drug was safe and well tolerated. No SAEs, deaths, or other major AEs were reported in the study. No subjects discontinued due to TEAEs. Of the 6 subjects, 3 subjects reported adverse events. Except for one AE (headache) of moderate intensity, all AEs (dizziness, headache, and agitation) were mild in intensity.

[0156] All subjects had no abnormal or clinically significant laboratory findings. There were no major changes in vital signs from baseline to 2 hours and 4 hours on Day 1, Day 2, Day 3, and Day 4, and no major changes in ECG parameters from baseline to pre-dose and 2 hours on Day 1, Day 2, Day 3, and Day 4. No subjects reported any suicidal ideation or events according to the Columbia Suicide Assessment Classification Algorithm.

[0157] in conclusion

[0158] Soanfito-T in both plasma and breast milk max After reaching the maximum concentration of serotonin, plasma and breast milk exposures followed a parallel monoexponential decline. max , AUC) was twice as high as that in plasma. In addition, the geometric mean milk:plasma ratio was 2.047. 1 / 2 It appears to be similar, about 5 hours. Soanfito is safe and well tolerated.

[0159] Further analysis of the data indicated that the infant daily dose was 0.112 mg / kg (based on a nominal infant weight of 6 kg) and that the relative infant dose (RID) was approximately 5.5% of the maternal weight-adjusted dose. Data were insufficient to determine the effects of Soanfito on breastfed infants or its effects on milk production.

[0160] The median cumulative amount excreted in breast milk over 72 hours was 0.67 mg, which is approximately 5.5% of the maternal dose adjusted for body weight. Approximately 78% and 98% of the total amount of sulphatol excreted in breast milk over 72 hours were excreted before 8 and 24 hours, respectively, with an apparent mean elimination half-life in breast milk of approximately 5 hours.

[0161] The developmental and health benefits of breastfeeding should be considered, as should the mother's clinical need for soanfitol and any potential adverse effects on the breastfed infant from soanfitol or the underlying maternal condition.

[0162] Infants exposed to Soanfito should be monitored for signs of agitation, sleeplessness, and decreased weight gain.

[0163] method

[0164] On Day -1, eligible subjects underwent baseline procedures. On Day 1, two hours after a light breakfast, subjects received a single dose of 150 mg of Soanfito with 240 mL of water. Subjects were required to fast for approximately four hours after the first dose; water was permitted except for one hour before and one hour after dosing with the study drug.

[0165] Before dose administration and after dose until multiple time intervals of 72 hours, the pharmacokinetic analysis of breast milk obtained from both breasts (by pumping) was evaluated. Blood samples were also collected for plasma Suoanfeituo quantitative and PK analysis at multiple time points before dose and after dose until 72 hours. Suoanfeituo breast milk and plasma concentrations were measured using a validated bioanalytical method. Throughout the study, safety was assessed by 12-lead ECG, vital signs measurement, Columbia-Suicide Severity Rating Scale (C-SSRS) and the incidence of adverse events (AEs).

[0166] The study drug is a yellow film-coated tablet containing the excipients hydroxypropylcellulose and magnesium stearate and a polymer film coating.

[0167] The total duration of the study (screening of the first subject to the safety follow-up of the last subject) was approximately 11 months.

[0168] Subjects had their vital signs (blood pressure, pulse rate, temperature, and respiratory rate) measured in a sitting or supine position and rested for at least 5 minutes before taking the measurements. The dominant arm was used for blood pressure and pulse rate measurements. On Day 1, vital signs were collected before the dose and approximately 2 hours (blood pressure and pulse) and 4 hours (blood pressure and pulse) after the dose.

[0169] Subjects underwent a 12-lead ECG in the supine position and rested for at least 10 minutes before measurements were taken. On Day 1, ECGs were collected before and approximately 2 hours after the dose.

[0170] Subjects must fast for at least 8 hours prior to chemistry and hematology blood draws. All clinical laboratory tests are performed at screening only (rescreening is permitted).

[0171] The Screening / Baseline C-SSRS version will be used at Screening and the version since last visit will be used on Days -1 and 2 (or at ET).

[0172] Milk collections occurred on days 1-4 -2 to 0 hours (pre-dose), 0-2, 2-4, 4-8, 8-12, 12-18, 24-32, 32-40, 40-48, and 48-72 hours post-dose.

[0173] Blood samples were collected for plasma PK evaluation at the following time points: pre-dose, 1, 1.5, 3, 6, 8.5, 10, 13, 15, 21, 24, 28, 36, 44, and 72 hours post-dose on Day 1. The general study methods are summarized in Table 6.

[0174] Table 6.

[0175]

[0176] The standardized meals included the required meals on Day -1, a light breakfast approximately 2.5 hours before dosing on Day 1 (completed approximately 2 hours before dosing), followed by lunch approximately 4 hours after dosing, dinner approximately 8 hours after dosing, and a snack approximately 11 hours after dosing and standardized meals thereafter.

[0177] Safety follow-up calls were recorded from 30 days prior to Screening until 5 to 7 days after sign-off from the study facility (on Day 4 or ET).

[0178] Adverse events were monitored throughout the study by safety assessments, observations, and subject reports, including a safety FU call-in 5-7 days after sign-off from the study facility on Day 4 or ET (i.e., Days 9-11).

[0179] Breast Milk Collection: Soanfito concentrations in breast milk and plasma were assessed based on pre- and post-dose samples collected on Days 1 to 4. Breast milk was collected from both breasts using an electronic breast pump during the following time intervals: from -2 to 0 hours pre-dose on Day 1, and 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 18, 18 to 24, 24 to 32, 32 to 40, 40 to 48, and 48 to 72 hours post-dose. The midpoint of each breast milk collection interval was used as the time variable.

[0180] During the designated time intervals, breast milk was collected as frequently as needed; however, at the end of each time interval, breast milk was expressed from both breasts and collected. At the end of each collection interval, all milk expressed from both breasts during that interval was pooled. The milk was thoroughly mixed by gently inverting the collection container 10 times to ensure homogeneity of milk composition. The weight and volume of milk collected during each time interval were also recorded.

[0181] Serial blood samples (4 mL) were collected and dispensed into labeled K2EDTA tubes. The actual blood collection time for all samples was recorded on the eCRF. The concentration of Soanfeituo in breast milk and plasma was determined using a validated bioanalytical method (LC-MS / MS) at the Origin Bioanalytical Laboratory. The analytical range (lower limit of quantification [LLOQ] to upper limit of quantification) of plasma Soanfeituo was 8.42 to 4210.00 ng / mL, and the analytical range (lower limit of quantification [LLOQ] to upper limit of quantification) of breast milk Soanfeituo was 10.0 to 8000 ng / mL.

[0182] use Version 8.3 (Certara, Inc., Princeton, New Jersey, USA) and / or Pharmacokinetic parameters were derived using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina, USA).

[0183] Subject criteria: Each subject who met the following criteria was enrolled in the study: healthy adult female aged 18 to 50 years (inclusive) at the time of consent; weighed at least 50 kg and had a body mass index (BMI) between 18 and 35 kg / m 2 (Inclusive); Between 10 days and 52 weeks postpartum (inclusive), after the delivery of a normal, healthy infant before the dosing time, and actively lactating from both breasts; If breastfeeding, agree to stop breastfeeding their (one or more) infants approximately 2 hours before dosing to approximately 72 hours after dosing, and resume breastfeeding after completing the study day 4 procedures, or decide to wean their infants before enrollment in the study; agree not to use nicotine-containing products, including tobacco (cigarettes, cigars, chewing tobacco, snuff), e-cigarettes, and nicotine lozenges / gum / patches, within 3 days before check-in on Day -1 and for the duration of the study; use a medically acceptable method of contraception for at least 2 months before dosing on Day 1, and agree to use a medically acceptable method of contraception throughout the study and for 30 days after completion of the study Participants were required to use a medically acceptable method of contraception during the study period; agree to follow a study-assigned diet while in the study; be able to understand and comply with study requirements; ensure their breastfed infant(s) are able to be bottle-fed prior to the start of study participation; agree to ensure their infant(s) have access to nutrition through stored breast milk or alternative nutrition sources as needed for the duration of the study; and be fully vaccinated at least 14 days after the last (or only) dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [COVID-19]) vaccine; or choose not to be vaccinated prior to the study, where participants who chose not to be fully vaccinated prior to the start of the study did not receive any doses of the COVID-19 vaccine and continued in the study.

[0184] Clinical laboratory tests were collected only at screening and included hematology, serum chemistry, urinalysis, and thyroid panel.

[0185] A complete physical examination included, at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal, and neurologic systems. Height and weight were also measured and recorded. BMI was calculated on-site at the Screening and Baseline / Randomization visits to verify eligibility.

[0186] Vital signs included oral temperature, pulse rate, respiratory rate, and BP. Clinically significant abnormal vital sign results reported during screening / randomization were recorded as medical history, and those reported after study drug were recorded as AEs.

[0187] Subjects were assessed for blood pressure and pulse measurements in a sitting or supine position and rested for at least 5 minutes before taking measurements. The dominant arm was used for blood pressure and pulse rate measurements. On Day 1, vital signs were collected before the dose and approximately 2 hours (blood pressure and pulse) and 4 hours (blood pressure and pulse) after the dose.

[0188] 12-lead ECGs were collected at screening, day -1, and up to day 4. A single 12-lead ECG was obtained using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT, and corrected QT intervals (QTc). Any abnormal safety assessment, including ECG readings, that was considered clinically significant in the medical and scientific judgment of the investigator was reported as an AE. The investigator must review the ECG and record it in the source file. Clinically significant abnormal ECG results reported during screening were recorded as medical history, and those reported after study drug were recorded as AEs.

[0189] All laboratory tests were performed according to the laboratory manual. The tests detailed in Table 7 were performed by the central laboratory. Additional tests could be performed at any time during the study as determined necessary by the investigator or as required by local regulations.

[0190] All laboratory tests with abnormal values ​​that are considered clinically significant (and considered by the investigator to be related to the study drug) during the study or within 14 days after the last dose of the study drug are repeated until the value returns to normal or baseline or is no longer considered clinically significant by the investigator or medical monitor. If a clinically significant value does not return to normal / baseline within a reasonable period of time determined by the investigator, the cause should be determined.

[0191] Table 7: Safety laboratory tests

[0192]

[0193] Urine drug screen (amphetamines, benzodiazepines,

[0194] Bitartrates, benzodiazepines Cocaine, urine at baseline (day -1)

[0195] marijuana, opiates, benzodiazepines

[0196] Cyclohexylpiperidine)

[0197] Breath alcohol test

[0198] ALB = albumin; ALK-P = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; Ca = calcium; CBC = complete blood count; CO2 = carbon dioxide; Cl = chloride; K = potassium; Na = sodium; WBC = white blood cell count.

[0199] * All subjects in the study were required to undergo pregnancy screening.

[0200] Statistics / Analysis

[0201] Unless otherwise indicated, descriptive statistics were used to summarize continuous data, including the number of subjects exposed (N) and the number to be summarized (n), mean, standard deviation (SD), median, minimum (min), maximum (max), geometric mean (GEM), coefficient of variation (CV%), and geometric coefficient of variation (CV%). Categorical variables were presented using counts and percentages. Analytical and summary outputs were generated using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina, USA).

[0202] The PK population consisted of all subjects who received study drug and provided post-dose breast milk or plasma PK data for at least one collection interval or time point. This population was used to summarize and tabulate evaluable PK concentration data and PK parameters. The safety population consisted of all subjects who received a dose of study drug. This population was used for demographic and baseline characteristics and for summarizing and tabulating safety data.

[0203] Descriptive statistics were used to summarize the pharmacokinetic concentrations and parameters, including n, arithmetic mean, SD, coefficient of variation (CV%), median, min, max, geometric mean (Geo-mean), and geometric coefficient of variation (Geo-CV%). max , only present n, median, minimum and maximum values.

[0204] Subjects with partial data were evaluated on a case-by-case basis to determine if there was sufficient data to reliably calculate PK parameters. In cases where milk collection was incomplete (partial / spilled samples, inaccurate information on the total milk volume of samples by time interval), the recovery by time interval was listed but not included in the summary, and the cumulative recovery was reported only through the most recent previous complete milk collection. Data by time interval during which the subject was unable to lactate (produce any milk) were treated as zero (for the affected time interval) in the total cumulative recovery calculation.

[0205] Plasma and milk concentrations were summarized using descriptive statistics. For the calculation of descriptive statistics, concentrations below the lower limit of quantitation (BLQ) were treated as follows:

[0206] Each summary statistic with one or more BLQ values ​​is calculated by assigning 1 / 2LLOQ to all values ​​less than LLOQ. If the calculated arithmetic (and geometric) mean is BLQ, the SD and CV% are presented as "ND" and the mean is presented as "BLQ." However, because a high proportion of BLQ values ​​may affect the SD; if more than 50% of values ​​are entered, the mean is not calculated for that time point, and only the BLQ value is presented again for the mean. Within the summary statistics, any minimum or median value calculated as BLQ is presented as BLQ in the summary display.

[0207] Concentrations collected outside the protocol-permitted sampling window were included in the descriptive statistics unless the PK scientist observed a bias substantial enough to affect the descriptive statistics. In this case, the excluded concentrations were identified in the CSR.

[0208] About drawing the arithmetic mean concentration distribution curve: Each time there is one or more BLQ values, the arithmetic mean is calculated by 1 The LLOQ is calculated by assigning a value of 1 / 2 to all BLQ values. If the calculated mean is the BLQ, that time point is plotted as zero in the mean pharmacokinetic curve. However, because a high proportion of BLQ values ​​may affect the SD, if a value exceeding 50% is entered, the mean is not calculated for that time point, and a value of zero is plotted again. A line with the LLOQ label is superimposed on the concentration axis to display the LLOQ level.

[0209] Safety analysis was based on the safety population. Secondary endpoints for evaluating subject safety and tolerability were the incidence of all subject-reported AEs and laboratory test results.

[0210] Adverse Events: Adverse events recorded in electronic case report forms (eCRFs) were coded as SOC and PT using the Medical Dictionary for Regulatory Activities (MedDRA). A treatment-emergent adverse event (TEAE) was defined as any event with an onset date on or after the day of the first dose of study drug, or any ongoing event that worsened in severity after the date of the first dose of study drug, or any event that was present at baseline but was subsequently considered by the investigator to be drug-related until the end of the study. The incidence of TEAEs is presented by severity, association with study drug, start and end dates, severity, and outcome. The investigator assessed the severity and relevance of each AE to the study drug. Columbia-Suicide Severity Rating Scale (C-SSRS) data were summarized and presented at scheduled visits. Additional safety analyses were performed as appropriate.

[0211] 12-lead ECG: The number and percentage of subjects with the following post-baseline clinically significant ECG interval abnormalities were summarized: ventricular rate ≥100 beats / minute or ≤60 beats / minute; PR interval ≥200 msec or ≤120 msec; QRS duration ≥100 msec or ≤80 msec; QT interval ≥440 msec or ≤350 msec; QTc Bazette and QTc Fredericia ≥470 msec or ≤330 msec; RR interval ≥1200 msec or ≤600 msec; and QTc Bazette and QTc Fredericia increased by >30 msec from study baseline values.

[0212] Vital Signs: Presentation of the following clinically significant vital sign abnormalities: mean systolic blood pressure ≥150 mmHg or ≤80 mmHg; mean diastolic blood pressure ≥95 mmHg or ≤60 mmHg; mean heart rate ≥120 bpm or ≤50 bpm; respiratory rate <10 breaths / minute or >24 breaths / minute; body temperature >37.9°C or <35.5°C; systolic and diastolic blood pressure changes >20% relative to study baseline values / recordings; pulse changes >20% relative to study baseline values / recordings; weight changes ≥7% from the subject's baseline value (weight loss / weight gain); and body temperature changes >1.8% from the subject's baseline temperature record.

[0213] Physical examination: The physical examination data of each subject are presented in a table. Clinically significant adverse changes (ie, worsening) found during physical examination after screening were recorded as AEs.

[0214] Disposition of Subjects. A total of 6 subjects were enrolled and treated in the study. All 6 subjects completed the study. No premature discontinuations were reported in the study. All 6 subjects received study drug (safety population) and provided post-dose breast milk or plasma PK data for at least one collection interval or time point (PK population). All 6 subjects were female and not of Hispanic or Latino ethnicity. The mean (SD) age, weight, height, and BMI for the total population were 28.7 (5.54) years, 79.15 (12.162) kg, 168.62 (6.013) cm, and 27.90 (4.513) kg / m, respectively. 2 .

[0215] Table 8: Demographics and Baseline Characteristics (Safety Population)

[0216]

[0217]

[0218] BMI = body mass index; N = number of subjects exposed

[0219] Note: Percentages are based on N.

[0220] Prior and Concomitant Medication: Two subjects took medications for AEs during the study: one subject received acetaminophen and the other received ibuprofen.

[0221] Medical and surgical history: A total of 5 of the 6 subjects had a medical and surgical history. Of these subjects, 1 subject had a history of appendectomy, cesarean section, and tubal ligation. One subject had asthma and a cesarean section. One subject had cholelithiasis, pancreatitis, and a cholecystectomy. One subject had an umbilical hernia repair, heartburn, and a cesarean section, and 1 subject had a vaginal delivery and hip pain caused by vaginal delivery.

[0222] References:

[0223] Czosnykowska- M., Królak-Olejnik, B., and Orczyk- M.(2018).Breast Milk Macronutrient Components in Prolonged Lactation.Nutrients,10(12),1893.Doi:10.3390 / nu10121893.

[0224] Jones BE (2000). Basic mechanisms of sleep-wake states. In: Kryger, MH; Roth, T.; and Dement, WC, eds. Principles and Practice of Sleep Medicine 3rd ed. Philadelphia: WB Saunders. pp. 134-154.

[0225] Li Y., Panossian, L.A., Zhang, J., Zhu, Y., Zhan, G., Chou, Y.T., Fenik, P., Bhatnagar, S., Piel, D.A., Beck, S.G., and Veasey, S. (2014). Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response. Sleep, 37(1), 51-64. Doi: 10.5665 / sleep.3306.

[0226] Lockwood P.A., Pauer, L., Scavone, J.M., Allard, M., Mendes da Costa, L., Alebic-Kolbah, T., Plotka, A., Alvey, C.W., and Chew, M.L. (2016). The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women. Journal of human lactation: official journal of International Lactation Consultant Association, 32(3), NP1-NP8. Doi: 10.1177 / 0890334415626148.

[0227] Posner K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., Currier, G.W., Melvin, G.A., Greenhill, L., Shen, S., and Mann, J.J. (2011). The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. The American journal of psychiatry, 168(12), 1266 - 1277. Doi:10.1176 / appi.ajp.2011.10111704.

[0228] Siegel J.M. Brainstem mechanisms generating REM sleep. In: Principals and Practice of Sleep Medicine, 2nd ed. Edited by M.K. Kryger, T.Roth, W.C. Dement. New York: Saunders, 2000.

[0229] Tsujino N., Tsunematsu, T., Uchigashima, M., Konno, K., Yamanaka, A., Kobayashi, K., Watanabe, M., Koyama, Y., and Sakurai, T. (2013). Chronic alterations in monoaminergic cells in the locus coeruleus in orexin neuron-ablated narcoleptic mice. PloS one, 8(7), e70012. Doi:10.1371 / journal.pone.0070012.

[0230] 美国食品药品监督管理局。药物评价和研究中心(2019年)。工业指南。临床泌乳研究:研究设计考量。草案指南。美国食品药品监督管理局药物评价和研究中心,马里兰州罗克维尔。

[0231] 美国食品药品监督管理局。药物评价和研究中心。2019年5月。工业指南。临床泌乳研究:研究设计考量。草案指南。美国食品药品监督管理局药物评价和研究中心,马里兰州罗克维尔。

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[0233] Wu X., Jackson, RT, Khan, SA, Ahuja, J., and Pehrsson, PR (2018). HumanMilk Nutrient Composition in the United States: Current Knowledge, Challenges, and Research Needs. Current developments in nutrition, 2(7), nzy025. Doi: 10.1093 / cdn / nzy025.

[0234] Zhu Y., Fenik, P., Zhan, G., Xin, R., and Veasey, SC (2015). Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea. Frontiers inneurology, 6, 109. Doi: 10.3389 / fneur.2015.00109.

[0235] The foregoing is illustrative of the present invention and should not be construed as limiting thereof. The present invention is defined by the following claims, including their equivalents. All publications, patent applications, patents, patent publications, and any other references cited herein are incorporated by reference in their entirety for the purposes of providing the teachings relevant to the sentence and / or paragraph in which the reference appears.

Claims

1. A method of reducing exposure to Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising: orally administering Soanfito to the subject at a daily dose of about 37.5 mg to about 300 mg; and The infant is fed breast milk from the subject at least about 5 hours after administration of Soanfitol to the subject, thereby reducing the infant's exposure to Soanfitol.

2. The method of claim 1, wherein the method provides an infant daily dose of Soanfito of about 0.3 mg or less.

3. The method of claim 1, wherein the method achieves a relative infant dose that is less than about 9% of the subject's weight-adjusted dose.

4. The method of claim 3, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

5. The method of claim 1, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

6. The method of claim 1, wherein the subject is 1 day to 24 months postpartum.

7. The method of claim 6, wherein the subject is 10 days to 12 months postpartum.

8. The method of claim 1, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

9. The method of claim 1, wherein the subject is a female between the ages of 18 and 45.

10. The method of claim 1, wherein the daily dose of Soanfito is 150 mg.

11. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a subject treated with Soanfitol, comprising: orally administering Soanfito to the subject at a daily dose between 37.5 mg and 300 mg; and The infant is fed breast milk from the subject for at least about 5 hours after administration of Soanfitol to the subject, thereby reducing the likelihood of an adverse event in the infant caused by Soanfitol.

12. The method of claim 11, wherein the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

13. The method of claim 11, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

14. The method of claim 11, wherein the method provides an infant daily dose of Soanfitol of about 0.3 mg or less.

15. The method of claim 11, wherein the relative infant dose is less than about 9% of the subject's weight-adjusted dose.

16. The method of claim 15, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

17. The method of claim 11, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

18. The method of claim 11, wherein the subject is 1 day to 24 months postpartum.

19. The method of claim 18, wherein the subject is 10 days to 12 months postpartum.

20. The method of claim 11, wherein the daily dose of Soanfito is 150 mg.

21. The method of claim 11, wherein the subject is a female between the ages of 18 and 45.

22. A method for treating a disorder treatable with Soanfito in a subject producing breast milk for feeding an infant, comprising: orally administering Soanfito to the subject at a daily dose between 37.5 mg and 300 mg; and Reducing the infant's exposure to Soanfitol and / or reducing the likelihood of an adverse event in the infant who is fed from the subject's breast milk comprises feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfitol to the subject.

23. The method of claim 22, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit / hyperactivity disorder, depression, or binge eating disorder.

24. The method of claim 22, wherein the method provides an infant daily dose of Soanfitol of about 0.3 mg or less.

25. The method of claim 22, wherein the method achieves a relative infant dose that is less than about 9% of the subject's weight-adjusted dose.

26. The method of claim 25, wherein the method achieves a relative infant dose that is less than about 5% of the subject's weight-adjusted dose.

27. The method of claim 22, wherein the infant does not experience restlessness, insomnia, anorexia, or decreased weight gain resulting from Soanfito exposure.

28. The method of claim 22, wherein the adverse event is one or more of agitation, insomnia, anorexia, or decreased weight gain.

29. The method of claim 22, wherein the subject is 1 day to 24 months postpartum.

30. The method of claim 29, wherein the subject is 10 days to 12 months postpartum.

31. The method of claim 22, wherein the subject is a female between the ages of 18 and 45.

32. The method of claim 22, wherein the daily dose of Soanfito is 150 mg.

33. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising: orally administering Soanfito to the mother at a once daily dose of about 150 mg; and feeding the infant breast milk obtained from the mother at least about 5 hours after administering Soanfito to the mother; wherein the infant daily dose of Soanfito is reduced to about 0.3 mg or less; and wherein the likelihood of adverse events in the infant being caused by Soanfito is reduced.

34. The method of claim 33, wherein the adverse event is agitation, insomnia, anorexia, or decreased weight gain.

35. The method of claim 33, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

36. The method of claim 33, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

37. The method of claim 33, wherein the lactating mother is 1 day to 24 months postpartum.

38. The method of claim 33, wherein the lactating mother is 10 days to 12 months postpartum.

39. The method of claim 33, wherein the lactating mother is between 18 and 45 years old.

40. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising: orally administering Soanfito to the mother at a dose of about 75 mg once daily; and feeding the infant breast milk obtained from the mother at least about 5 hours after administering Soanfito to the mother; wherein the infant daily dose of Soanfito is reduced to about 0.15 mg or less; and wherein the likelihood of adverse events in the infant being caused by Soanfito is reduced.

41. The method of claim 40, wherein the adverse event is agitation, insomnia, anorexia, or decreased weight gain.

42. The method of claim 40, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

43. The method of claim 40, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

44. The method of claim 40, wherein the lactating mother is 1 day to 24 months postpartum.

45. The method of claim 40, wherein the lactating mother is 10 days to 12 months postpartum.

46. ​​The method of claim 40, wherein the lactating mother is between 18 and 45 years old.

47. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising: orally administering Soanfito to the mother at a once daily dose of about 150 mg; and feeding the infant breast milk obtained from the mother at least about 5 hours after administering Soanfito to the mother; wherein the infant daily dose of Soanfito is reduced to about 0.3 mg or less; and wherein said infant's exposure to soanfito from said breast milk is reduced.

48. The method of claim 47, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

49. The method of claim 47, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

50. The method of claim 47, wherein the lactating mother is 1 day to 24 months postpartum.

51. The method of claim 47, wherein the lactating mother is 10 days to 12 months postpartum.

52. The method of claim 47, wherein the lactating mother is between 18 and 45 years old.

53. A method of treating excessive daytime sleepiness, attention deficit hyperactivity disorder, binge eating disorder, depression, or cognitive impairment in a nursing mother feeding her infant with her breast milk, comprising: orally administering Soanfito to the mother at a once daily dose of about 75 mg; and feeding the infant breast milk obtained from the mother at least about 5 hours after administering Soanfito to the mother; wherein the infant daily dose of Soanfito is reduced to about 0.15 mg or less; and wherein said infant's exposure to soanfito from said breast milk is reduced.

54. The method of claim 53, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

55. The method of claim 53, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work disorder, depression, or Parkinson's disease.

56. The method of claim 53, wherein the lactating mother is 1 day to 24 months postpartum.

57. The method of claim 53, wherein the lactating mother is 10 days to 12 months postpartum.

58. The method of claim 53, wherein the nursing mother is between 18 and 45 years old.

59. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; wherein the infant daily dose of Soanfito is reduced to about 0.3 mg or less; and wherein the likelihood of adverse events in the infant being caused by Soanfito is reduced.

60. The method of claim 59, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

61. The method of claim 59, wherein the subject is 1 day to 24 months postpartum.

62. The method of claim 59, wherein the subject is 10 days to 12 months postpartum.

63. The method of claim 59, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

64. The method of claim 63, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

65. The method of claim 63, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

66. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising: orally administering Soanfito to the subject at a dose of about 75 mg once daily; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; wherein the infant daily dose of Soanfito is reduced to about 0.15 mg or less; and wherein the likelihood of adverse events in the infant being caused by Soanfito is reduced.

67. The method of claim 66, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

68. The method of claim 66, wherein the subject is 1 day to 24 months postpartum.

69. The method of claim 66, wherein the subject is 10 days to 12 months postpartum.

70. The method of claim 66, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

71. The method of claim 70, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

72. The method of claim 70, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

73. A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; wherein the infant daily dose of Soanfito is reduced to about 0.3 mg or less; and wherein said infant's exposure to soanfito from said breast milk is reduced.

74. The method of claim 73, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

75. The method of claim 73, wherein the subject is 1 day to 24 months postpartum.

76. The method of claim 73, wherein the subject is 10 days to 12 months postpartum.

77. The method of claim 73, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

78. The method of claim 77, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

79. The method of claim 77, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

80. (New) A method for treating a disorder amenable to treatment with Soanfito in a postpartum human subject who is producing breast milk, comprising: orally administering Soanfito to the subject at a dose of about 75 mg once daily; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; wherein the infant daily dose of Soanfito is reduced to about 0.15 mg or less; and wherein said infant's exposure to soanfito from said breast milk is reduced.

81. The method of claim 80, wherein the infant does not experience restlessness, sleeplessness, anorexia, or decreased weight gain caused by Soanfitol from the breast milk.

82. The method of claim 80, wherein the subject is 1 day to 24 months postpartum.

83. The method of claim 80, wherein the subject is 10 days to 12 months postpartum.

84. The method of claim 80, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

85. The method of claim 84, wherein the excessive daytime sleepiness is due to narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

86. The method of claim 84, wherein the cognitive impairment is due to narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

87. A method of reducing the risk of agitation in an infant fed breast milk obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 150 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

88. The method of claim 87, wherein the infant does not experience agitation resulting from Soanfitol exposure.

89. The method of claim 87, wherein the subject is 1 day to 24 months postpartum.

90. The method of claim 87, wherein the subject is 11 days to 12 months postpartum.

91. The method of claim 87, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

92. The method of claim 91, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

93. The method of claim 91, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

94. The method of claim 87, wherein the subject is being treated with Soanfito to improve wakefulness.

95. The method of claim 87, wherein the subject is a female between the ages of 18 and 50.

96. A method of reducing the risk of agitation in a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 75 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

97. The method of claim 96, wherein the infant does not experience agitation resulting from Soanfitol exposure.

98. The method of claim 96, wherein the subject is 1 day to 24 months postpartum.

99. The method of claim 96, wherein the subject is 11 days to 12 months postpartum.

100. The method of claim 96, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

101. The method of claim 100, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

102. The method of claim 100, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

103. The method of claim 96, wherein the subject is being treated with Soanfito to improve wakefulness.

104. The method of claim 96, wherein the subject is a female between the ages of 18 and 50.

105. A method of reducing the risk of insomnia in a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 150 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

106. The method of claim 105, wherein the infant does not experience insomnia caused by Soanfito exposure.

107. The method of claim 105, wherein the subject is 1 day to 24 months postpartum.

108. The method of claim 105, wherein the subject is 11 days to 12 months postpartum.

109. The method of claim 105, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

110. The method of claim 109, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

111. The method of claim 109, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

112. The method of claim 105, wherein the subject is being treated with Soanfito to improve wakefulness.

113. The method of claim 105, wherein the subject is a female between the ages of 18 and 50.

114. A method of reducing the risk of insomnia in an infant fed breast milk obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 75 mg; and feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfito to the subject; The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

115. The method of claim 114, wherein the infant does not experience insomnia caused by Soanfito exposure.

116. The method of claim 114, wherein the subject is 1 day to 24 months postpartum.

117. The method of claim 114, wherein the subject is 11 days to 12 months postpartum.

118. The method of claim 114, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

119. The method of claim 118, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

120. The method of claim 118, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

121. The method of claim 114, wherein the subject is being treated with Soanfito to improve wakefulness.

122. The method of claim 114, wherein the subject is a female between the ages of 18 and 50.

123. A method of reducing the risk of anorexia and / or decreased weight gain in a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 150 mg; and feeding the infant with breast milk obtained from the subject at least about 5 hours after administration of Soanfitol to the subject, The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

124. The method of claim 123, wherein the infant does not experience anorexia, decreased weight gain, or weight loss resulting from Soanfito exposure.

125. The method of claim 123, wherein the subject is 1 day to 24 months postpartum.

126. The method of claim 123, wherein the subject is 11 days to 12 months postpartum.

127. The method of claim 123, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

128. The method of claim 127, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

129. The method of claim 127, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

130. The method of claim 123, wherein the subject is being treated with Soanfito to improve wakefulness.

131. The method of claim 123, wherein the subject is a female between the ages of 18 and 50.

132. A method of reducing the risk of anorexia and / or decreased weight gain in a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 75 mg; and feeding the infant with breast milk obtained from the subject at least about 5 hours after administration of Soanfitol to the subject, The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

133. The method of claim 132, wherein the infant does not experience anorexia, decreased weight gain, or weight loss resulting from Soanfito exposure.

134. The method of claim 132, wherein the subject is 1 day to 24 months postpartum.

135. The method of claim 132, wherein the subject is 11 days to 12 months postpartum.

136. The method of claim 132, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

137. The method of claim 136, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

138. The method of claim 136, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

139. The method of claim 132, wherein the subject is being treated with Soanfito to improve wakefulness.

140. The method of claim 132, wherein the subject is a female between the ages of 18 and 50.

141. A method of preventing a decrease in the number of feedings and / or a decrease in the volume of milk consumed by a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 150 mg; and feeding the infant with breast milk obtained from the subject at least about 5 hours after administration of Soanfitol to the subject, The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

142. The method of claim 141, wherein the infant does not experience a decrease in the number of feedings and / or a decrease in the volume of milk consumed as a result of Soanfito exposure.

143. The method of claim 141, wherein the subject is 1 day to 24 months postpartum.

144. The method of claim 141, wherein the subject is 11 days to 12 months postpartum.

145. The method of claim 141, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

146. The method of claim 145, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

147. The method of claim 145, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

148. The method of claim 141, wherein the subject is being treated with Soanfito to improve wakefulness.

149. The method of claim 141, wherein the subject is a female between the ages of 18 and 50.

150. A method of preventing a decrease in the number of feedings and / or a decrease in the volume of milk consumed by a breastfed infant obtained from a subject treated with Soanfito, comprising: orally administering Soanfito to the subject at a daily dose of about 75 mg; and feeding the infant with breast milk obtained from the subject at least about 5 hours after administration of Soanfitol to the subject, The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

151. The method of claim 150, wherein the infant does not experience a decrease in the number of feedings and / or a decrease in the volume of milk consumed as a result of Soanfito exposure.

152. The method of claim 150, wherein the subject is 1 day to 24 months postpartum.

153. The method of claim 150, wherein the subject is 11 days to 12 months postpartum.

154. The method of claim 150, wherein the subject is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, binge eating disorder, Parkinson's disease, depression, or cognitive impairment.

155. The method of claim 154, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

156. The method of claim 154, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, Parkinson's disease, or attention deficit hyperactivity disorder.

157. The method of claim 150, wherein the subject is being treated with Soanfito to improve wakefulness.

158. The method of claim 150, wherein the subject is a female between the ages of 18 and 50.

159. A method of preventing an infant of a nursing human mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, the method comprising not feeding the infant breast milk obtained within at least about 3.5 hours of the mother receiving a once daily oral dose of about 150 mg of Soanfitol, wherein the median T of Soanfitol excreted in the breast milk is max It is about 1.1 hours, The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

160. The method of claim 159, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

161. The method of claim 159, wherein the infant does not experience agitation due to exposure to Soanfitol.

162. The method of claim 159, wherein the infant does not experience sleeplessness due to exposure to Soanfito.

163. The method of claim 159, wherein the infant does not experience anorexia and / or decreased weight gain due to exposure to Soanfitol.

164. The method of claim 159, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:

1.

165. The method of claim 159, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

166. The method of claim 159, wherein breast milk produced by the nursing mother during the at least about 3.5 hours that the mother receives the once daily oral dose of Soanfito is expressed and discarded.

167. The method of claim 159, wherein the mother is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

168. The method of claim 167, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

169. The method of claim 167, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

170. The method of claim 159, wherein the mother is being treated with Soanfito to improve wakefulness.

171. The method of claim 159, wherein the nursing mother is from about 1 day to about 24 months postpartum.

172. The method of claim 159, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

173. The method of claim 159, wherein the lactating mother is between 18 and 45 years old.

174. A method of preventing an infant of a nursing human mother being treated with Soanfitol from being exposed to peak concentrations of Soanfitol excreted in breast milk, the method comprising not feeding the infant breast milk obtained within at least about 3.5 hours of the mother receiving a once daily oral dose of about 75 mg of Soanfitol, wherein the median T of Soanfitol excreted in the breast milk is max It is about 1.1 hours, The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

175. The method of claim 174, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

176. The method of claim 174, wherein the infant does not experience agitation due to exposure to Soanfitol.

177. The method of claim 174, wherein the infant does not experience insomnia due to exposure to Soanfito.

178. The method of claim 174, wherein the infant does not experience anorexia and / or decreased weight gain due to exposure to Soanfito.

179. The method of claim 174, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:

1.

180. The method of claim 174, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

181. The method of claim 174, wherein breast milk produced by the nursing mother during the at least about 3.5 hours that the mother receives the once daily oral dose of Soanfito is expressed and discarded.

182. The method of claim 174, wherein the mother is being treated with Soanfitol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

183. The method of claim 182, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

184. The method of claim 182, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

185. The method of claim 174, wherein the mother is being treated with Soanfito to improve wakefulness.

186. The method of claim 174, wherein the nursing mother is from about 1 day to about 24 months postpartum.

187. The method of claim 174, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

188. The method of claim 174, wherein the lactating mother is between 18 and 45 years old.

189. A method of reducing exposure to soanfitol from breast milk of an infant receiving breast milk from a nursing human mother who is being treated with a once daily dose of about 150 mg of soanfitol for a disorder amenable to treatment with soanfitol, the method comprising feeding the infant breast milk obtained from the mother at least about 5 hours after administration of soanfitol to the mother, wherein the infant's exposure to soanfitol is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of soanfitol, and The daily dose of Soanfito for infants was reduced to about 0.3 mg or less.

190. The method of claim 189, wherein the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose.

191. The method of claim 189, wherein the breast milk is obtained from the mother at least about 7 hours after administration of Soanfitol to the mother.

192. The method of claim 189, wherein the breast milk is obtained from the mother at least about 10 hours after administration of Soanfitor to the mother.

193. The method of claim 189, wherein breast milk produced by the nursing mother during the at least about 5 hours after administration of Soanfitol to the mother is expressed and discarded.

194. The method of claim 189, wherein the infant does not experience agitation due to exposure to Soanfitol.

195. The method of claim 189, wherein the infant does not experience insomnia due to exposure to Soanfito.

196. The method of claim 189, wherein the infant does not experience anorexia and / or decreased weight gain due to exposure to Soanfito.

197. The method of claim 189, wherein the mother is being treated with Soanfitol for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

198. The method of claim 197, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

199. The method of claim 197, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

200. The method of claim 189, wherein the mother is being treated with Soanfito to improve wakefulness.

201. The method of claim 189, wherein the nursing mother is from about 1 day to about 24 months postpartum.

202. The method of claim 189, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

203. The method of claim 189, wherein the lactating mother is between 18 and 45 years old.

204. A method of reducing exposure to soanfitol from breast milk of an infant receiving breast milk from a nursing human mother who is being treated with a once daily dose of about 75 mg of soanfitol for a disorder amenable to treatment with soanfitol, the method comprising feeding the infant breast milk obtained from the mother at least about 5 hours after administration of soanfitol to the mother, wherein the infant's exposure to soanfitol is reduced by at least about 50% compared to the exposure that would result from feeding the infant breast milk obtained from the mother less than 5 hours after administration of soanfitol, and The daily dose of Soanfito for infants was reduced to about 0.15 mg or less.

205. The method of claim 204, wherein the resulting relative infant dose is about 2% or less of the maternal weight-adjusted dose.

206. The method of claim 204, wherein the breast milk is obtained from the mother at least about 7 hours after administration of Soanfito to the mother.

207. The method of claim 204, wherein the breast milk is obtained from the mother at least about 10 hours after administration of Soanfitol to the mother.

208. The method of claim 204, wherein breast milk produced by the nursing mother during the at least about 5 hours after administration of Soanfitol to the mother is expressed and discarded.

209. The method of claim 204, wherein the infant does not experience agitation due to exposure to Soanfitol.

210. The method of claim 204, wherein the infant does not experience insomnia due to exposure to Soanfito.

211. The method of claim 204, wherein the infant does not experience anorexia and / or decreased weight gain due to exposure to Soanfitol.

212. The method of claim 204, wherein the mother is being treated with Soanfito for excessive daytime sleepiness, narcolepsy, obstructive sleep apnea, shift work disorder, attention deficit hyperactivity disorder, Parkinson's disease, binge eating disorder, depression, or cognitive impairment.

213. The method of claim 212, wherein the excessive daytime sleepiness is associated with narcolepsy, obstructive sleep apnea, shift work, depression, or Parkinson's disease.

214. The method of claim 212, wherein the cognitive impairment is associated with narcolepsy, obstructive sleep apnea, shift work, or Parkinson's disease.

215. The method of claim 204, wherein the mother is being treated with Soanfito to improve wakefulness.

216. The method of claim 204, wherein the lactating mother is from about 1 day to about 24 months postpartum.

217. The method of claim 204, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

218. The method of claim 204, wherein the lactating mother is between 18 and 45 years old.

219. A method of treating excessive daytime sleepiness in a lactating human mother whose infant is at risk for an adverse event caused by the mother's excessive daytime sleepiness, and wherein the lactating human mother desires to breastfeed the infant, the method comprising: a) determining the mother's Epworth Sleepiness Scale (ESS) total score and whether the mother experiences sleep attacks while caring for the infant, (b) providing the mother who has an ESS total score of 15 or greater and experiences sleep attacks while caring for the infant with a starting dose of Soanfitol: 37.5 mg once daily if the excessive daytime sleepiness is associated with obstructive sleep apnea, or 75 mg once daily if the excessive daytime sleepiness is associated with narcolepsy, and doubling the dose at intervals of at least 3 days up to 150 mg once daily; and (c) feeding the infant breast milk obtained from the mother at least about 3.5 hours after the mother is administered soanfitol, thereby avoiding exposure of the infant to the maximum concentration of soanfitol in the breast milk, The median T of Soanfito excreted in breast milk max It is about 1.1 hours, and The infant daily dose of Soanfito was reduced to about 0.3 mg or less after the 150 mg dose, to about 0.15 mg or less after the 75 mg dose, and to about 0.08 mg or less after the 37.5 mg dose.

220. The method of claim 219, wherein the lactating mother experiences a decrease in ESS total score of 5 or more.

221. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while holding the infant.

222. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while feeding the infant.

223. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of sleep episodes while nursing the infant.

224. The method of claim 219, wherein the nursing mother experiences a decrease in the frequency of automatic movements while caring for the infant.

225. The method of claim 219, wherein the infant is not fed breast milk obtained within at least about 5 hours of the mother receiving the once daily oral dose of Soanfito.

226. The method of claim 219, wherein the infant does not experience agitation due to exposure to soanfitol in the breast milk.

227. The method of claim 219, wherein the infant does not experience sleeplessness due to exposure to Soanfitol in the breast milk.

228. The method of claim 219, wherein the infant does not experience anorexia and / or decreased weight gain due to exposure to soanfitol in the breast milk.

229. The method of claim 219, wherein the soanfito is excreted in the breast milk with a milk to plasma AUC ratio of approximately 2:

1.

230. The method of claim 219, wherein the elimination half-life of Soanfidol excreted in said breast milk is about 5 hours.

231. The method of claim 219, wherein breast milk produced by the mother during the at least about 3.5 hours after administration of Soanfitol to the mother is expressed and discarded.

232. The method of claim 219, wherein the lactating mother is from about 1 day to about 24 months postpartum.

233. The method of claim 219, wherein the lactating mother is between about 10 days and about 52 weeks postpartum.

234. The method of claim 219, wherein the lactating mother is between 18 and 45 years old.

235. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a human subject treated with Soanfitol, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and feeding the infant breast milk from the subject at least about 5 hours after administration of Soanfito to the subject, The cumulative amount of Soanfidol excreted in breast milk within 8 hours is reduced to about 0.26 mg or less.

236. The method of claim 235, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

237. The method of claim 235, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

238. The method of claim 235, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

239. The method of claim 235, wherein the lactating mother is 1 day to 24 months postpartum.

240. The method of claim 239, wherein the subject is 10 days to 52 weeks postpartum.

241. A method for reducing the likelihood of adverse events caused by Soanfitol in a breastfed infant obtained from a human subject treated with Soanfitol, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and feeding the infant breast milk from the subject at least about 5 hours after administration of Soanfito to the subject, The cumulative amount of Soanfidol excreted in breast milk within 24 hours is reduced to about 0.35 mg or less.

242. The method of claim 241, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

243. The method of claim 241, wherein the subject is being treated with Soanfito for narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, attention-deficit / hyperactivity disorder, cognitive impairment, depression, or binge eating disorder.

244. The method of claim 241, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

245. The method of claim 241, wherein the lactating mother is 1 day to 24 months postpartum.

246. The method of claim 245, wherein the subject is 10 days to 52 weeks postpartum.

247. A method for treating a disorder treatable with Soanfito in a human subject producing breast milk for feeding an infant, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and reducing the infant's exposure to Soanfitol and / or reducing the likelihood of an adverse event in the infant who is fed from the subject's breast milk, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfitol to the subject, The cumulative median amount of sulphatol excreted in breast milk within 8 hours was reduced to approximately 0.26 mg or less.

248. The method of claim 247, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit / hyperactivity disorder, depression, or binge eating disorder.

249. The method of claim 247, wherein the infant does not experience restlessness, insomnia, or decreased weight gain due to Soanfito exposure.

250. The method of claim 247, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

251. The method of claim 247, wherein the subject is 1 day to 24 months postpartum.

252. The method of claim 251, wherein the subject is 10 days to 52 weeks postpartum.

253. The method of claim 247, wherein the subject is a female between the ages of 18 and 45.

254. A method for treating a disorder treatable with Soanfeto in a human subject producing breast milk for feeding an infant, comprising: orally administering Soanfito to the subject at a once daily dose of about 150 mg; and reducing the infant's exposure to Soanfitol and / or reducing the likelihood of an adverse event in the infant who is fed from the subject's breast milk, comprising feeding the infant breast milk obtained from the subject at least about 5 hours after administering Soanfitol to the subject, The cumulative median amount of Soanfidol excreted in breast milk within 24 hours was reduced to about 0.35 mg or less.

255. The method of claim 254, wherein the disorder treatable with Soanfito is narcolepsy, excessive daytime sleepiness, obstructive sleep apnea, cognitive impairment, attention-deficit / hyperactivity disorder, depression, or binge eating disorder.

256. The method of claim 254, wherein the infant does not experience restlessness, insomnia, or decreased weight gain resulting from Soanfito exposure.

257. The method of claim 254, wherein the adverse event is one or more of agitation, insomnia, or decreased weight gain.

258. The method of claim 254, wherein the subject is 1 day to 24 months postpartum.

259. The method of claim 258, wherein the subject is 10 days to 52 weeks postpartum.

260. The method of claim 254, wherein the subject is a female between the ages of 18 and 45.

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